Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• the invention relates to bicyclic heterocycles of the general formula their tautomers, their stereoisomers including their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, which have valuable pharmacological properties, preferably anti-aggregation effects, medicaments containing these compounds and their use and processes for their preparation.
• Y1 is a nitrogen atom or a carbon atom substituted by the radical R1, where R1 represents a hydrogen atom or an alkyl group
• Y2 is a nitrogen atom substituted by the radical R1, where R1 is defined as mentioned above, an oxygen or sulfur atom
• R10 represents an alkyl or phenylalkyl group each having 1 to 3 carbon atoms in the alkyl part, and their salts.
• Preferred compounds of the above general formula I are those in which Y1 is a nitrogen atom or a carbon atom substituted by the radical R1, where R1 represents a hydrogen atom or an alkyl group, Y2 is a nitrogen atom substituted by the radical R1, where R1 is defined as mentioned above, an oxygen or sulfur atom,
• Particularly preferred compounds of the general formula I above are those in which Y1 is a nitrogen atom or a carbon atom substituted by the radical R1, where R1 represents a hydrogen atom, a methyl or ethyl group, Y2 is a nitrogen atom substituted by the radical R1, where R1 is defined as mentioned above, an oxygen or sulfur atom,
• B is a phenylene group optionally substituted by a fluorine, chlorine or bromine atom, by a methyl or ethyl group, in which a methine group can
• the catalytic hydrogenation is preferably carried out in a suitable solvent such as methanol, methanol / water, acetic acid, ethyl acetate, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically excited hydrogen, e.g. of hydrogen in the presence of Raney nickel, platinum, rhodium or palladium / carbon, at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 80 ° C.
• a suitable solvent such as methanol, methanol / water, acetic acid, ethyl acetate, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide
• an acid such as hydrochloric acid
• catalytically excited hydrogen e.g. of hydrogen in the presence of Raney nickel, platinum, rhodium or palladium / carbon
• any reactive groups present such as hydroxyl, carboxy, phosphono, O-alkylphosphono, amino, alkylamino, imino or amidino groups, can be replaced by customary groups during the reaction Protecting groups are protected, which are split off again after the implementation.
• the trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group, as protective residues for a carboxyl group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, as protective residues for a phosphono group an alkyl group such as the methyl, ethyl, isopropyl or n-butyl group, the phenyl or benzyl group, as a protective radical for an amidino group optionally substituted by an alkyl group, the benzyloxycarbonyl group and as a protective radical for an amino, alkylamino or imino group, the formyl, acetyl, trifluoroacetyl, allyloxycarbonyl, ethoxycarbon
• the subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or by means of ether cleavage, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
• an aqueous solvent e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water
• an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
• a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
• a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
• a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or ether.
• a trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution or aqueous lithium hydroxide solution, if appropriate in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.
• an acid such as hydrochloric acid
• a solvent such as acetic acid at temperatures between 50 and 120 ° C.
• sodium hydroxide solution or aqueous lithium hydroxide solution if appropriate in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.
• An allyloxycarbonyl radical is split off by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an allyl group acceptor such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C.
• a catalytic amount of tetrakis (triphenylphosphine) palladium (O) preferably in a solvent such as tetrahydrofuran and preferably in the presence of an allyl group acceptor such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C.
• a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
• Only one alkyl radical is split off from an O, O'-dialkylphosphono group, for example using sodium iodide in a solvent such as acetone, ethyl methyl ketone, acetonitrile or dimethylformamide at temperatures between 40 and 150 ° C., but preferably at temperatures between 60 and 100 ° C.
• a solvent such as acetone, ethyl methyl ketone, acetonitrile or dimethylformamide
• Both alkyl radicals are split off from an O, O'-dialkylphosphono group, for example using iodotrimethylsilane, bromotrimethylsilane or chlorotrimethylsilane / sodium iodide in a solvent such as methylene chloride, chloroform or acetonitrile at temperatures between 0 ° C. and the boiling point of the reaction mixture, but preferably at temperatures between 20 and 60 ° C.
• the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
• cis / trans mixtures can be separated into their cis and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
• the cis / trans mixtures obtained can be chromatographed into their cis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in " Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 stereogenic centers due to their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers separate which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
• the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
• a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols
• optically active alcohols are, for example, (+) - or (-) - menthol
• optically active acyl radicals in amides are, for example, (+) - or (-) - menthyloxycarbonyl.
• the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
• suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
• the new compounds of the formula I obtained in this way if they contain a carboxyl group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
• the bases here are, for example, sodium hydroxide, potassium hydroxide, Arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine are considered.
• Some of the compounds used as starting materials are known from the literature or can be obtained by methods known from the literature (see examples), for example by cyclizing an appropriate o-pyridyldiamine with an appropriate carboxylic acid derivative or by reacting an appropriate carboxylic acid derivative with an appropriate 3-halopiperid-4-one or 5-halo-azepin-4-one.
• a bicyclic derivative thus obtained can then be converted into a desired starting compound by means of hydrolysis, alkylation and / or acylation.
• a compound of general formula Ia is prepared by alkylating a corresponding benzimidazole of general formula I with a corresponding alkyl or phenylalkyl halide such as methyl iodide or benzyl bromide in a solvent such as dimethyl sulfoxide and in the presence of a base such as potassium tert-butoxide at temperatures between 0 and 50 ° C, preferably at room temperature.
• a base such as potassium tert-butoxide
• the new bicyclic heterocycles of the general formula I and their salts have valuable properties.
• the free and bound ligand is separated by centrifugation and quantified by scintillation counting.
• the inhibition of the 3H-BIBU 52 binding by the test substance is determined from the measured values.
• donor blood is drawn from an anti-cubital vein and anticoagulated with trisodium citrate (final concentration 13 mM).
• the blood is centrifuged at 170 xg for 10 minutes and the supernatant platelet-rich plasma (PRP) is removed.
• the residual blood is centrifuged again sharply to obtain plasma.
• the PRP is diluted 1:10 with autologous plasma. 750 ⁇ l are incubated with 50 ⁇ l physiological saline, 100 ⁇ l test substance solution, 50 ⁇ l 14C-sucrose (3,700 Bq) and 50 ⁇ l 3H-BIBU 52 (final concentration: 5 nM) at room temperature for 20 minutes.
• BIBU 52 final concentration: 30 ⁇ M
• the samples are centrifuged at 10,000 xg for 20 seconds and the supernatant is removed. 100 ⁇ l of this are measured to determine the free ligand.
• the pellet is dissolved in 500 ul 0.2N NaOH, 450 ul are mixed with 2 ml scintillator and 25 ul 5N HCl and measured. The residual plasma remaining in the pellet is determined from the 14C content, the bound ligand from the 3H measurement. After subtracting the non-specific Binding, the pellet activity is plotted against the concentration of the test substance and the concentration for 50 ° inhibition of binding is determined.
• Platelet aggregation is measured according to the method of Born and Cross (J. Physiol. 170 , 397 (1964)) in platelet-rich plasma from healthy test subjects. To inhibit coagulation, the blood is mixed with 3.14% sodium citrate in a volume ratio of 1:10.
• the course of the decrease in the optical density of the platelet suspension is measured and recorded photometrically after the addition of the aggregation-triggering substance.
• the rate of aggregation is inferred from the angle of inclination of the density curve.
• the point of the curve at which the greatest light transmittance is present is used to calculate the "optical density".
• the amount of collagen is chosen to be as small as possible, but in such a way that an irreversible reaction curve results.
• the commercial collagen from Hormonchemie, Kunststoff, is used.
• the plasma is incubated with the substance at 37 ° C. for 10 minutes.
• An EC50 is determined graphically from the measurement numbers obtained, which relates to a 50% change in the "optical density" in the sense of an inhibition of aggregation.
• the compounds according to the invention are well tolerated since, for example, none of the 3 animals tested died after intravenous administration of 30 mg / kg of the compounds of Examples 4 and 4 (1) to the mouse.
• the new cyclic urea derivatives of the general formula I and their physiologically tolerable salts are suitable for combating or preventing diseases in which smaller or larger cell aggregates occur or cells -Matrix interactions play a role, for example in combating or preventing venous and arterial thrombosis, cerebrovascular diseases, pulmonary embolism, myocardial infarction, arteriosclerosis, osteoporosis and the metastasis of tumors and the therapy of genetic or acquired disorders in the interactions of cells with one another or with solid structures.
• These are also suitable for accompanying therapy in thrombolysis with fibrinolytics or vascular interventions such as transluminal angioplasty or in the therapy of shock conditions, psoriasis, diabetes and inflammation.
• the dose is between 0.1 ⁇ g and 30 mg / kg body weight, preferably 1 ⁇ g to 15 mg / kg body weight, with up to 4 doses per day.
• the compounds of the formula I prepared according to the invention optionally in combination with other active substances such as thromboxane receptor antagonists and thromboxane synthesis inhibitors or their combinations, serotonin antagonists, ⁇ -receptor antagonists, alkyl nitrates such as glycerol trinitrate, phosphodiesterase inhibitors, prostacyclin and their analogues, such as tibrin, Fibrin Prourokinase, urokinase, streptokinase, or anticoagulants such as heparin, dermatan sulfate, activated protein C, vitamin K antagonists, hirudin, inhibitors of thrombin or other activated coagulation factors, together with one or more iner
• reaction is carried out with 1- (ethoxycarbonyloxy) ethyl chloride in dimethyl sulfoxide.
• composition Active ingredient 2.5 mg Mannitol 50.0 mg Water for injections ad 1.0 ml
• Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.
• composition Active ingredient 35.0 mg Mannitol 100.0 mg Water for injections ad 2.0 ml
• Active ingredient and mannitol are dissolved in water. After filling, freeze-drying.
• the ready-to-use solution is dissolved with water for injections.
• composition (1) Active ingredient 50.0 mg (2) milk sugar 98.0 mg (3) corn starch 50.0 mg (4) polyvinyl pyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0 mg ⁇
• composition (1) Active ingredient 350.0 mg (2) milk sugar 136.0 mg (3) corn starch 80.0 mg (4) polyvinyl pyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg ⁇
• composition (1) Active ingredient 50.0 mg (2) Dried corn starch 58.0 mg (3) powdered milk sugar 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg ⁇
• (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
• This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.
• composition (1) Active ingredient 350.0 mg (2) Dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg ⁇
• (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
• This powder mixture is filled in a size 0 hard gelatin capsule on a capsule filling machine.

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• 1993
  • 1993-07-22 DE DE4324580A patent/DE4324580A1/de not_active Withdrawn
• 1994
  • 1994-07-19 EP EP94111221A patent/EP0639575A1/fr not_active Withdrawn
  • 1994-07-20 CA CA002128464A patent/CA2128464A1/fr not_active Abandoned
  • 1994-07-21 JP JP6168505A patent/JPH0770137A/ja active Pending
• 1995
  • 1995-07-31 US US08/509,248 patent/US5607944A/en not_active Expired - Fee Related

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